Open AccessKami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism
Author(s) -
Qingyun Guo,
Ken Ebihara,
Takafumi Shimodaira,
Hironori Fujiwara,
Kazufumi Toume,
Dya Fita Dibwe,
Suresh Awale,
Ryoko Araki,
Takeshi Yabe,
Kinzo Matsumoto
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0211266
Subject(s) - allopregnanolone , gabaa receptor , bicuculline , neuroactive steroid , dopamine , dopaminergic , allosteric modulator , gabaergic , antagonist , pharmacology , prefrontal cortex , receptor antagonist , medicine , endocrinology , neuroscience , receptor , psychology , allosteric regulation , cognition
Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5α-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABA A receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D 1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D 2 receptor antagonist sulpiride and GABA A receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABA A receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.